The purpose of this project is to determine the natural course of renal disease in type 2 diabetes mellitus in the Pima Indians and to identify the underlying pathogenetic mechanisms involved in the initiation and progression of renal disease in this type of diabetes. This project, in part, represents an extension of work previously reported as Project Number Z01 DK 69037. Glomerular function was measured over a 4-year period in 194 Pima Indians selected to represent stages in the development and progression of diabetic renal disease. Follow-up was extended for an additional 24 months in the 57 subjects with microalbuminuria to characterize the evolution and mechanisms of progressive diabetic glomerular injury. Subjects underwent serial determinations of albuminuria and GFR, and a subset of them underwent morphometric analysis of glomeruli in two biopsies separated by an interval of 48 months. GFR declined by 17% and renal plasma flow by 17% over 60-84 months, regardless of whether or not subjects progressed to macroalbuminuria. Neither glomerular volume nor fractional mesangial volume changed over 48 months, but the prevalence of global glomerulosclerosis doubled and the number of podocytes per glomerulus declined significantly from 547 to 356. Single nephron Kf declined by 20% and was the major determinant of the decline in GFR. Sieving studies in these patients demonstrated no loss of the size-selective barrier in subjects with microalbuminuria, but an abrupt appearance of a shunt at an albumin-to-creatinine ratio of about 3000 mg/g. Shunt size in macroalbuminuric patients correlated with the extent of foot process broadening. These results suggest that although microalbuminuria heralds progressive renal injury, it is not due to defects in the size permselectivity of the glomerular barrier, but rather to changes in either glomerular charge selectivity, tubular handling of filtered proteins, or a combination of these two factors.